Deficiency of Antinociception and Excessive Grooming Induced by Acute Immobilization Stress in Per1 Mutant Mice

Acute stressors induce changes in numerous behavioral parameters through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Several important hormones in paraventricular nucleus of the hypothalamus (PVN) play the roles in these stress-induced reactions. Corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and corticosterone are considered as molecular markers for stress-induced grooming behavior. Oxytocin in PVN is an essential modulator for stress-induced antinociception. The clock gene, Per1, has been identified as an effecter response to the acute stresses, but its function in neuroendocrine stress systems remains unclear. In the present study we observed the alterations in grooming and nociceptive behaviors induced by acute immobilization stress in Per1 mutant mice and other genotypes (wild types and Per2 mutant). The results displayed that stress elicited a more robust effect on grooming behavior in Per1 mutant mice than in other genotypes. Subsequently, the obvious stress-induced antinociception was observed in the wild-type and Per2 mutant mice, however, in Per1 mutant, this antinociceptive effects were partially-reversed (mechanical sensitivity), or over-reversed to hyperalgesia (thermal sensitivity). The real-time qPCR results showed that in PVN, there were stress-induced up-regulations of Crh, Avp and c-fos in all of genotypes; moreover, the expression change of Crh in Per1 mutant mice was much larger than in others. Another hormonal gene, Oxt, was up-regulated induced by stress in wild-type and Per2 mutant but not in Per1 mutant. In addition, the stress significantly elevated the serum corticosterone levels without genotype-dependent differences, and accordingly the glucocorticoid receptor gene, Nr3c1, expressed with a similar pattern in PVN of all strains. Taken together, the present study indicated that in acute stress treated Per1 mutant mice, there are abnormal hormonal responses in PVN, correlating with the aberrant performance of stress-induced behaviors. Therefore, our findings suggest a novel functional role of Per1 in neuroendocrine stress system, which further participates in analgesic regulation

Dissociation of Analgesic and Hormonal Responses to Forced Swim Stress Using Opioid Receptor Knockout Mice

International audienceExposure to stress triggers hormonal and behavioral responses. It has been shown that the endogenous opioid system plays a role in some physiological reactions to stress. The opioid system was described to mediate analgesia induced by mild stressors and to modulate the activation of the hypothalamic-pituitary-adrenal axis. Our study assessed the contribution of opioid receptors in stress-induced analgesia and adrenocorticotropic hormone (ACTH) and corticosterone release by a genetic approach. We performed a parallel analysis of mice deficient in mu, delta, or kappa opioid receptors, as well as of triple opioid receptor knockout mice, following exposure to a mild stress (3-min swim at 32 degrees C). In wild-type mice, stress elicited an increase in jumping latency on the hot plate, which was influenced by gender and genetic background. This analgesic response was reversed both by naloxone and by the triple mutation, and decreased in mu and delta opioid receptor knockout females. In wild-type females, stress also delayed front- and hindpaw behaviors in the hot plate test and increased tail-flick latency in the tail immersion test. Opioid receptor deletion however did not affect these stress responses. In addition, stress produced an increase in ACTH and corticosterone plasma levels. This endocrine response remained unchanged in all mutant strains. Therefore our data indicate that, under our stress conditions, the endogenous opioid system is recruited to produce some analgesia whereas it does not influence hypothalamic-pituitary-adrenal axis activity. This implies that brain circuits mediating analgesic and hormonal responses to stress can be dissociated

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

BACKGROUND: The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS: In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS: Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). CONCLUSIONS: Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group